tbuckley/cabot-search huggingface dataset:
The affordability of lecanemab, an amyloid-targeting therapy for Alzheimer's disease: an EADC-EC viewpoint
Authors: Linus Jönsson, Anders Wimo, Ron Handels, Gunilla Johansson, Mercè Boada, Sebastiaan Engelborghs, Lutz Frölich, Frank Jessen, Patrick Gavin Kehoe, Milica Kramberger, Alexandre de Mendonςa, Pierre Jean Ousset, Nikolaos Scarmeas, Pieter Jelle Visser, Gunhild Waldemar, Bengt Winblad
Journal: The Lancet Regional Health - Europe (2023)

Lecanemab, an anti-amyloid antibody with effects on biomarker and clinical endpoints in early Alzheimer's Disease (AD), was granted accelerated approval by the FDA in 2023 and regulatory review in Europe is ongoing. We estimate the population potentially eligible for treatment with lecanemab in the 27 EU countries to 5.4 million individuals. Treatment costs would exceed 133 billion EUR per year if the drug is priced similarly as in the United States, amounting to over half of the total pharmaceutical expenditures in the EU. This pricing would be unsustainable; the ability to pay for high-priced therapies varies substantially across countries. Pricing similarly to what has been announced for the United States may place the drug out of reach for patients in some European countries. Disparities in access to novel amyloid-targeting agents may further deepen the inequalities across Europe in health outcomes. As representatives of the European Alzheimer's Disease Consortium Executive Committee, we call for pricing policies that allow eligible patients across Europe to access important innovations, but also continued investments in research and development. Infrastructure to follow up the usage of new therapies in routine care and new payment models may be needed to address affordability and inequalities in patient access.
Investigating structural attributes of drug encapsulated microspheres with quantitative X-ray imaging
Authors: Andrew G. Clark, Ruifeng Wang, Josh Lomeo, Yan Wang, Aiden Zhu, Mike Shen, Quanying Bao, Diane J. Burgess, Bin Qin, Shawn Zhang
Journal: Journal of Controlled Release (2023)

The intra-sphere and inter-sphere structural attributes of controlled release microsphere drug products can greatly impact their release profile and clinical performance. In developing a robust and efficient method to characterize the structure of microsphere drug products, this paper proposes X-ray microscopy (XRM) combined with artificial intelligence (AI)-based image analytics. Eight minocycline loaded poly(lactic-co-glycolic acid) (PLGA) microsphere batches were produced with controlled variations in manufacturing parameters, leading to differences in their underlying microstructures and their final release performances. A representative number of microspheres samples from each batch were imaged using high resolution, non-invasive XRM. Reconstructed images and AI-assisted segmentation were used to determine the size distribution, XRM signal intensity, and intensity variation of thousands of microspheres per sample. The signal intensity within the eight batches was nearly constant over the range of microsphere diameters, indicating high structural similarity of spheres within the same batch. Observed differences in the variation of signal intensity between different batches suggests inter-batch non-uniformity arising from differences in the underlying microstructures associated with different manufacturing parameters. These intensity variations were correlated with the structures observed from higher resolution focused ion beam scanning electron microscopy (FIB-SEM) and the in vitro release performance for the batches. The potential for this method for rapid at-line and offline product quality assessment, quality control, and quality assurance is discussed.
Quantitative Detection of Promoter Hypermethylation of Multiple Genes in the Tumor, Urine, and Serum DNA of Patients with Renal Cancer
Authors: Mohammad Obaidul Hoque, Shahnaz Begum, Ozlem Topaloglu, Carmen Jeronimo, Elizabeth Mambo, William H. Westra, J. A. Califano, David Sidransky
Journal: Cancer Research (2004)

Abstract Aberrant promoter hypermethylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of human cancers and is a promising marker for cancer detection. We investigated the feasibility of detecting aberrant DNA methylation in the urine and serum samples of renal cancer patients. We examined the tumor and the matched urine and serum DNA for aberrant methylation of nine gene promoters (CDH1, APC, MGMT, RASSF1A, GSTP1, p16, RAR-β2, and ARF) from 17 patients with primary kidney cancer by quantitative fluorogenic real-time PCR. An additional 9 urine samples (total, 26) and 1 serum sample (total, 18) also were tested from renal cancer patients. Urine from 91 patients without genitourinary cancer and serum from 30 age-matched noncancer individuals were used as controls. Promoter hypermethylation of at least two of the genes studied was detected in 16 (94%) of 17 primary tumors. Aberrant methylation in urine and serum DNA generally was accompanied by methylation in the matched tumor samples. Urine samples from 91 control subjects without evidence of genitourinary cancer revealed no methylation of the MGMT, GSTP1, p16, and ARF genes, whereas methylation of RAR-β2, RASSF1A, CDH1, APC, and TIMP3 was detected at low levels in a few control subjects. Overall, 23 (88%) of 26 urine samples and 12 (67%) of 18 serum samples from cancer patients were methylation positive for at least one of the genes tested. By combination of urine or serum analysis of renal cancer patients, hypermethylation was detected in 16 of 17 patients (94% sensitivity) with high specificity. Our findings suggest that promoter hypermethylation in urine or serum can be detected in the majority of renal cancer patients. This noninvasive high-throughput approach needs to be evaluated in large studies to assess its value in the early detection and surveillance of renal cancer.
Post‐translational modifications of histones: Mechanisms, biological functions, and therapeutic targets
Authors: Ruiqi Liu, Jiajun Wu, Haiwei Guo, Weiping Yao, Shuang Li, Yanwei Lu, Yongshi Jia, Xiaodong Liang, Jianming Tang, Haibo Zhang
Journal: MedComm (2023)

Abstract Histones are DNA‐binding basic proteins found in chromosomes. After the histone translation, its amino tail undergoes various modifications, such as methylation, acetylation, phosphorylation, ubiquitination, malonylation, propionylation, butyrylation, crotonylation, and lactylation, which together constitute the “histone code.” The relationship between their combination and biological function can be used as an important epigenetic marker. Methylation and demethylation of the same histone residue, acetylation and deacetylation, phosphorylation and dephosphorylation, and even methylation and acetylation between different histone residues cooperate or antagonize with each other, forming a complex network. Histone‐modifying enzymes, which cause numerous histone codes, have become a hot topic in the research on cancer therapeutic targets. Therefore, a thorough understanding of the role of histone post‐translational modifications (PTMs) in cell life activities is very important for preventing and treating human diseases. In this review, several most thoroughly studied and newly discovered histone PTMs are introduced. Furthermore, we focus on the histone‐modifying enzymes with carcinogenic potential, their abnormal modification sites in various tumors, and multiple essential molecular regulation mechanism. Finally, we summarize the missing areas of the current research and point out the direction of future research. We hope to provide a comprehensive understanding and promote further research in this field.
The role of MRI technology in liver evaluation for NAFLD patients: Advancements and opportunities
Authors: Masato Yoneda, Atsushi Nakajima
Journal: Hepatology (2023)

Department of Gastroenterology and Hepatology, Yokohama City University Hospital, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, Japan Financial Support: This work was supported by Grant-in-Aid for Scientific Research C Grant Number 21K08012. List of Abbreviations: MRE, magnetic resonance elastography; MRI, magnetic resonance imaging; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PDFF, proton density fat fraction; qMRI, quantitative MRI Correspondence Masato Yoneda, 3-9 Fukuura Kanazawaku, Yokohama, Japan 236-0033. E-mail: [email protected]
Type 1 Diabetes Incidence and Risk in Children With a Diagnosis of COVID-19
Authors: Andreas Weiss, Ewan Donnachie, Andreas Beyerlein, Anette-G. Ziegler, Ezio Bonifacio
Journal: JAMA (2023)

This study used a population-based individual patient data set that included diagnoses of COVID-19 to determine whether there was a temporal association between COVID-19 and type 1 diabetes in children.
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Journal: JAMA Network Open (2023)

Cedric Edwards, MD; Gregory L. Hundemer, MD, MPH; William Petrcich, MSc; Mark Canney, MB, BCh, BAO, PhD; Greg Knoll, MD, MSc; Kevin Burns, MD; Ann Bugeja, MD; Manish M. Sood, MD, MSc
Coronary revascularization for heart failure with coronary artery disease: A systematic review and meta‐analysis of randomized trials
Authors: Antonio Iaconelli, Pierpaolo Pellicori, Pasquale Dolce, Matteo Busti, Aureliano Ruggio, Nadia Aspromonte, Domenico D'Amario, Mattia Galli, Giuseppe Princi, Elisabetta Caiazzo, Asma O.M. Rezig, Pasquale Maffia, Giovanni Pecorini, Filippo Crea, John G.F. Cleland
Journal: European Journal of Heart Failure (2023)

Coronary artery disease (CAD) is a common cause of heart failure (HF). Whether coronary revascularization improves outcomes in patients with HF receiving guideline-recommended pharmacological therapy (GRPT) remains uncertain; therefore, we conducted a systematic review and meta-analysis of relevant randomized controlled trials (RCTs).We searched in public databases for RCTs published between 1 January 2001 and 22 November 2022, investigating the effects of coronary revascularization on morbidity and mortality in patients with chronic HF due to CAD. All-cause mortality was the primary outcome. We included five RCTs that enrolled, altogether, 2842 patients (most aged <65 years; 85% men; 67% with left ventricular ejection fraction ≤35%). Overall, compared to medical therapy alone, coronary revascularization was associated with a lower risk of all-cause mortality (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.79-0.99; p = 0.0278) and cardiovascular mortality (HR 0.80, 95% CI 0.70-0.93; p = 0.0024) but not the composite of hospitalization for HF or all-cause mortality (HR 0.87, 95% CI 0.74-1.01; p = 0.0728). There were insufficient data to show whether the effects of coronary artery bypass graft surgery or percutaneous coronary intervention were similar or differed.For patients with chronic HF and CAD enrolled in RCTs, the effect of coronary revascularization on all-cause mortality was statistically significant but neither substantial (HR 0.88) nor robust (upper 95% CI close to 1.0). RCTs were not blinded, which may bias reporting of the cause-specific reasons for hospitalization and mortality. Further trials are required to determine which patients with HF and CAD obtain a substantial benefit from coronary revascularization by either coronary artery bypass graft surgery or percutaneous coronary intervention.
<i>KLK11</i> ichthyosis: large truncal hyperkeratotic pigmented plaques underscore a distinct autosomal dominant disorder of cornification
Authors: Takuya Takeichi, Yasutoshi Ito, John Y W Lee, Chiaki Murase, Yusuke Okuno, Yoshinao Muro, John A McGrath, Masashi Akiyama
Journal: British Journal of Dermatology (2023)

Recently, Gong et al. reported two substitutions, p.(Gly50Glu) and p.(Gly50Arg), located at the last amino acid of the estimated signal peptide in kallikrein11 (KLK11) in three independent ichthyosiform erythroderma or erythrokeratoderma pedigrees (Gong et al., Br J Dermatol, 2023). Here, we present a further case of autosomal dominant congenital ichthyosiform erythroderma caused by the p.(Gly50Glu) substitution in KLK11; the patient had sharply demarcated pigmented hyperkeratotic lesions. Thus, p.(Gly50Glu) in KLK11 might represent a recurrent variant underlying this recently reported autosomal dominant disorder of cornification, and the large hyperkeratotic pigmented plaques seen in all patients may represent a pathognomonic part of the phenotype.
Impact of type 2 diabetes on mortality, cause of death, and treatment in chronic lymphocytic leukemia
Authors: Emelie Curovic Rotbain, Cristine Allmer, Klaus Rostgaard, Michael Asger Andersen, Noomi Vainer, Caspar da Cunha‐Bang, Sameer A. Parikh, Kari G. Rabe, Henrik Hjalgrim, Henrik Frederiksen, Susan L. Slager, Carsten Utoft Niemann
Journal: American Journal of Hematology (2023)

Abstract Age‐related comorbid conditions are exceedingly common in patients with chronic lymphocytic leukemia (CLL). As the prevalence of type 2 diabetes (T2D) is predicted to double during the next two decades, a better understanding of the interplay between CLL and T2D is of increasing importance. In this study, analyses were performed in parallel in two separate cohorts, based on Danish national registers and the Mayo Clinic CLL Resource. The primary outcomes were overall survival (OS) from time of CLL diagnosis, OS from time of treatment, and time to first treatment (TTFT), studied using Cox proportional hazard regression analysis and Fine‐Gray regression analysis. In the Danish CLL cohort, the prevalence of T2D was 11%, in the Mayo CLL cohort, it was 12%. Patients with CLL and T2D had shorter OS both from time of diagnosis and from first‐line treatment for were less likely to receive treatment for CLL compared with patients with CLL and without T2D. The increased mortality was largely driven by an increased risk of death due to infections, especially in the Danish cohort. The findings of this study emphasize a substantial subgroup of CLL patients with co‐occurring T2D with an inferior prognosis and a possible unmet treatment need requiring additional interventions and further research.
Distinct Epithelial-Innate Immune Cell Transcriptional Circuits Underlie Airway Hyperresponsiveness in Asthma
Authors: Ryan C. Murphy, Ying Lai, Matthew Liu, Taha Al-Shaikhly, Matthew C. Altman, William A. Altemeier, Charles W. Frevert, Jason S. Debley, Adrian M. Piliponsky, Steven F. Ziegler, Sina A. Gharib, Teal S. Hallstrand
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: Indirect airway hyperresponsiveness (AHR) is a highly specific feature of asthma, but the underlying mechanisms responsible for driving indirect AHR remain incompletely understood. Objectives: To identify differences in gene expression in epithelial brushings obtained from individuals with asthma who were characterized for indirect AHR in the form of exercise-induced bronchoconstriction (EIB). Methods: RNA-sequencing analysis was performed on epithelial brushings obtained from individuals with asthma with EIB (n = 11) and without EIB (n = 9). Differentially expressed genes (DEGs) between the groups were correlated with measures of airway physiology, sputum inflammatory markers, and airway wall immunopathology. On the basis of these relationships, we examined the effects of primary airway epithelial cells (AECs) and specific epithelial cell–derived cytokines on both mast cells (MCs) and eosinophils (EOS). Measurements and Main Results: We identified 120 DEGs in individuals with and without EIB. Network analyses suggested critical roles for IL-33–, IL-18–, and IFN-γ–related signaling among these DEGs. IL1RL1 expression was positively correlated with the density of MCs in the epithelial compartment, and IL1RL1, IL18R1, and IFNG were positively correlated with the density of intraepithelial EOS. Subsequent ex vivo modeling demonstrated that AECs promote sustained type 2 (T2) inflammation in MCs and enhance IL-33–induced T2 gene expression. Furthermore, EOS increase the expression of IFNG and IL13 in response to both IL-18 and IL-33 as well as exposure to AECs. Conclusions: Circuits involving epithelial interactions with MCs and EOS are closely associated with indirect AHR. Ex vivo modeling indicates that epithelial-dependent regulation of these innate cells may be critical in indirect AHR and modulating T2 and non-T2 inflammation in asthma.
FDA Approval Summary: Mirvetuximab Soravtansine-Gynx for FRα-Positive, Platinum-Resistant Ovarian Cancer
Authors: Asma Dilawari, Mirat Shah, Gwynn Ison, Haley Gittleman, Mallorie H. Fiero, Ankit Shah, Salaheldin S. Hamed, Junshan Qiu, Jingyu Yu, Wimolnut Manheng, Tiffany K. Ricks, Rajan Pragani, Arulvathani Arudchandran, Paresma Patel, Shadia Zaman, Arpita Roy, Shyam Kalavar, Soma Ghosh, William F. Pierce, Nam Atiqur Rahman, Shenghui Tang, Bronwyn D. Mixter, Paul G. Kluetz, Richard Pazdur, Laleh Amiri-Kordestani
Journal: Clinical Cancer Research (2023)

Abstract On November 14, 2022, the FDA granted accelerated approval to mirvetuximab soravtansine-gynx for treatment of adult patients with folate receptor-α (FRα)-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received one to three prior systemic therapies. The VENTANA FOLR1 (FOLR-2.1) RxDx Assay was approved as a companion diagnostic device to select patients for this indication. Approval was based on Study 0417 (SORAYA, NCT04296890), a single-arm, multicenter trial. In 104 patients with measurable disease who received mirvetuximab soravtansine-gynx, the overall response rate was 31.7% [95% confidence interval (CI), 22.9–41.6] with a median duration of response of 6.9 months (95% CI, 5.6–9.7). Ocular toxicity was included as a Boxed Warning in the U.S. Prescribing Information (USPI) to alert providers of the risks of developing severe ocular toxicity including vision impairment and corneal disorders. Pneumonitis and peripheral neuropathy were additional important safety risks included as Warnings and Precautions in the USPI. This is the first approval of a targeted therapy for FRα-positive, platinum-resistant ovarian cancer and the first antibody–drug conjugate approved for ovarian cancer. This article summarizes the favorable benefit–risk assessment leading to FDA's approval of mirvetuximab soravtansine-gynx.
New drug approvals for 2022: Synthesis and clinical applications
Authors: Shuo Yuan, Dan‐Dan Shen, Rui Jia, Ju‐Shan Sun, Jian Song, Hong‐Min Liu
Journal: Medicinal Research Reviews (2023)

Abstract The U.S. Food and Drug Administration has approved a total of 37 new drugs in 2022, which are composed of 20 chemical entities and 17 biologics. In particular, 20 chemical entities, including 17 small molecule drugs, 1 radiotherapy, and 2 diagnostic agents, provide privileged scaffolds, breakthrough clinical benefits, and a new mechanism of action for the discovery of more potent clinical candidates. The structure‐based drug development with clear targets and fragment‐based drug development with privileged scaffolds have always been the important modules in the field of drug discovery, which could easily bypass the patent protection and bring about improved biological activity. Therefore, we summarized the relevant valuable information about clinical application, mechanism of action, and chemical synthesis of 17 newly approved small molecule drugs in 2022. We hope this timely and comprehensive review could bring about creative and elegant inspiration on the synthetic methodologies and mechanism of action for the discovery of new drugs with novel chemical scaffolds and extended clinical indications.
Clinical Utility of Tau Positron Emission Tomography in the Diagnostic Workup of Patients With Cognitive Symptoms
Authors: Ruben Smith, Douglas Hägerström, Daria Pawlik, Gregory Klein, Jonas Jögi, Tomas Ohlsson, Erik Stomrud, Oskar Hansson
Journal: JAMA Neurology (2023)

Importance It is important to determine the added clinical value for tau positron emission tomography (PET) in the diagnostic workup of patients with cognitive symptoms before widespread implementation in clinical practice. Objective To prospectively study the added clinical value of PET detecting tau pathology in Alzheimer disease (AD). Design, Setting, and Participants This prospective cohort study (Swedish BioFINDER-2 study) took place from May 2017 through September 2021. A total of 878 patients with cognitive complaints were referred to secondary memory clinics in southern Sweden and then recruited to the study. In total, 1269 consecutive participants were approached, but 391 did not meet inclusion criteria or did not complete the study. Exposures Participants underwent a baseline diagnostic workup, including clinical examination, medical history, cognitive testing, blood and cerebrospinal fluid sampling, magnetic resonance imaging of the brain, and a tau PET ([ 18 F]RO948) scan. Main Outcomes and Measures The primary end points were change in diagnosis and change in AD drug therapy or other drug treatment between the pre- and post-PET visits. A secondary end point was the change in diagnostic certainty between the pre- and post-PET visits. Results A total of 878 participants with a mean age of 71.0 (SD, 8.5) years (491 male [56%]) were included. The tau PET result led to a change in diagnoses in 66 participants (7.5%) and a change in medication in 48 participants (5.5%). The study team found an association with overall increased diagnostic certainty after tau PET in the whole data set (from 6.9 [SD, 2.3] to 7.4 [SD, 2.4]; P &amp;amp;lt; .001). The certainty was higher in participants with a pre-PET diagnosis of AD (from 7.6 [SD, 1.7] to 8.2 [SD, 2.0]; P &amp;amp;lt; .001) and increased even further in participants with a tau PET positive result supporting an AD diagnosis (from 8.0 [SD, 1.4] to 9.0 [SD, 0.9]; P &amp;amp;lt; .001). The association with tau PET results had the largest effect sizes in participants with pathological amyloid-β (Aβ) status, whereas no significant change in diagnoses was seen in participants with normal Aβ status. Conclusions and Relevance The study team reported a significant change in diagnoses and patient medication when tau PET was added to an already extensive diagnostic workup that included cerebrospinal fluid AD biomarkers. Including tau PET was associated with a significant increase in certainty of underlying etiology. The effect sizes for certainty of etiology and diagnosis were largest in the Aβ-positive group and the study team suggests that clinical use of tau PET be limited to populations with biomarkers indicating Aβ positivity.
Effect of Torsemide Versus Furosemide on Symptoms and Quality of Life Among Patients Hospitalized for Heart Failure: The TRANSFORM-HF Randomized Clinical Trial
Authors: Stephen J. Greene, Eric J. Velazquez, Kevin J. Anstrom, Robert M. Clare, Tracy A. DeWald, Mitchell A. Psotka, Andrew P. Ambrosy, Gerin R. Stevens, John J. Rommel, Tamas Alexy, Fassil Ketema, Dong-Yun Kim, Patrice Desvigne-Nickens, Bertram Pitt, Eric L. Eisenstein, Robert J. Mentz
Journal: Circulation (2023)

Loop diuretics are a primary therapy for the symptomatic treatment of heart failure (HF), but whether torsemide improves patient symptoms and quality of life better than furosemide remains unknown. As prespecified secondary end points, the TRANSFORM-HF trial (Torsemide Comparison With Furosemide for Management of Heart Failure) compared the effect of torsemide versus furosemide on patient-reported outcomes among patients with HF.